The kinetic disposition of morphine and its relation to norepinephrine, dopamine and serotonin will be evaluated in brain sections of non-tolerant and tolerant rats. Gas chromatography-mass fragmentography will serve as the primary analytical tool for morphine, heroin and biogenic amines. In addition 90% enriched N-methyl-C14 morphine and randomly labelled H-3 morphine will be utilized to account for non-extractable morphine, metabolites and irreversibly bound fractions. Highly sensitive and specific analytical techniques are necessary to measure the log-linear terminal phase of elimination of morphine from rat brain, which is defined by pharmacokinetic parameters and easily saturable high affinity binding of morphine to "opiate receptors". The hypothesis will be tested that the severity of withdrawal symptoms in morphine or heroin addition is correlated to the rate of change of "opiate receptor" occupancy by morphine. Further pharmacokinetic parameters of morphine and heroin will be measured in rat and dog cerebrospinal fluid. It will be attempted to develop a model which allows us to calculate doses of morphine or heroin, which prevent withdrawal symptoms without sustained dependance.